Certain pyridyl-thiazolinyl phosphates and the corresponding phosphorothioates

ABSTRACT

Pyridyl-(2)-phosphates and phosphorothicates are disclosed which have in 5-position at the pyridine nucleus a thiazolinyl-(2) grouping and which are insecticidal and acaricidal agents useful in the control of insects and Acarinae, and more particularly of cattle ticks. Compositions containing these novel compounds, methods for controlling insects and Acarinae therewith, and novel 2-hydroxy- and 2-mercapto-5-thiazolinyl-(2&#39;)-pyridines useful as intermediates in their production are also described.

United States Patent 3,535,325 CERTAIN PYRIDYL-TI-IIAZOLINYL PHOS- PHATES AND THE CORRESPONDING PHOSPHOROTHIOATES Kurt Gubler and Urs Meyer, Riehen, and Hans Ulrich Brechbuhler, Basel, Switzerland, assignors to Geigy Chemical Corporation, Ardsley, N.Y., a corporation of New York No Drawing. Filed Sept. 25, 1968, Ser. No. 762,643 Claims priority, application Switzerland, Sept. 29, 1967,

13,636/67 Int. Cl. C0711 31/50 US. Cl. 260-294.8 2 Claims ABSTRACT OF THE DISCLOSURE Pyridyl-(2)-phosphates and phosphorothioates are disclosed which have in 5-position at the pyridine nucleus a thiazolinyl-(Z) grouping and which are insecticidal and acaricidal agents useful in the control of insects and arcarinae, and more particularly of cattle ticks. Compositions containing these novel compounds, methods for controlling insects and acarinae therewith, and novel 2- hydroxyand Z-mercapto-S-thiazolinyl-(2)-pyridines useful as intermediates in their production are also described.

DETAILED DISCLOSURE (Rah;

wherein R and R independently of each other each represent a lower alkyl or a lower alkenyl radical, or a lower alkyl radical substituted by halogen of an atomic number of at most and/or lo-Wer alkoxy,

R represents hydrogen, halogen of an atomic number of at most 35 or a lower alkyl radical,

X and Y independently of each other each represent oxygen or sulphur, and n represents 1 or 2,

and their addition salts with inorganic acids, organic sulphonic and organic sulphuric acids, are good to very good contact and stomach poisons for insects and spiders, and have more particularly an excellent long lasting action against insects of the families Muscidae, Stomoxidae and Culicidae, e.g. against polyvalent resistent and normally sensitive house flies (Musca domestica), stable flies (Stomoxys calcitrans) and mosquitoes (e.g. Aedes aegyptii, Culex fatigans, Anopheles stephensi), against insects of the families Curculionidae, Bruchididae, Dermestidae, Tenebrionidae and Chrysomelidae, e.g. granary weevils (Sitophilus granarius), bean beetles (Bruchidius obteclus), larder beetles (Demestes vulpinus), yellow meal worms (Tenebrio molitor), Colorado potato beetles (Leptinotarsa decemlineata) and their larval stages,

"ice

against insects of the family Pyralididae, e.g. Mediterranean flour moths (Ep/zestia kt't'hniella), of the family Blattidae, e.g. cockroaches (Phyllodromia germanica, Periplaneta americana, Blatta orientalis) against insects of the Aphididae family, e.g. leaf aphids (Aphis fabae), of the Pseudococcidae family, e.g. citrus mealy bugs (Planococcus citri) and of the Locustidae family, e.g. desert locusts (Locusta migratoria). Tests on the leaf aphids and locusts indicate also a systemic action.

Moreover, the compounds of Formula I have a good action against the larval and adult stages of acarinae, especially ticks, e.g. of the families Ixodidae and Argasidae.

The range of action of the active substances mentioned is broadened and, in particular, the insecticidal and acaricidal action is improved in admixture with synergists which enhance the aforesaid action without being necessarily themselves insecticides or acaricides such as succinic acid dibutyl ester or piperonyl butoxide or With similarly acting auxiliaries such as olive oil or peanut oil. Also, the insecticidal action can be substantially broadened and adapted to given circumstances by the addition of other insecticides such as phosphoric acid esters, phosphonic acid esters, thiophosphoric acid esters and dithiophosphoric acid esters and the amides of these acids, carbamic acid esters, halogenated hydrocarbons such as dichlorodiphenyltrichloroethane and analogs thereof, pyrethrins and their synergists.

In the general Formula I by lower alkyl radicals R R and R those having 1 to 4 carbon atoms such as the methyl, ethyl, a propyl or butyl radical, are to be understood, R being preferably methyl. R and R as lower alkenyl radicals, can be, e.g. the allyl, methallyl, or a propenyl radical. By a halogenoalkyl radical, also radicals having 1 to 4 carbon atoms are to be understood, which radicals are monoor poly-substituted by chlorine and/ or bromine; preferred is the B-chloroethyl radical. An alkoxy radical as substituent of a lower alkyl radical R and R is also one having 1 to 4 carbon atoms, preferably the methoxy radical.

In most preferred compounds of Formula I R represents hydrogen.

The thiazolinyl-pyridyl radical in the compounds of this invention is always a (2'-thiazolinyl)-pyridyl-(2) radical of the formula In a first process, the new esters of general Formula I are produced by reacting a thiazolinyl-pyridine derivative of the general Formula II M HYLNfl (II) in the presence of a base with a phosphorochloridate or phosphorochloridothioate of the general Formula III RiO X R20 (III) or by reacting a salt (oxide or mercaptide) of such a thiazolinyl pyridine derivative with such a halide of the general Formula III, whereby the symbols R R R X, Y and n in Formulae II and III have the meanings given in Formula I, and Hal represents chlorine or bromine.

In a second process, the new thiazolinyl-pyridyl phosphates and phosphorothioates of the general Formula I can also be produced by conversion of a cyanopyridine derivative of the general Formula IV HY N (IV) wherein R Y and n are defined as in Formula I, or a salt of this cyanopyridine derivative with a base, with a phosphorochloridate of the general Formula III (Ra)n as described in US. Pat. 3,326,752 to R. H. Rigterink, and reaction of the latter with cysteamine (HSCH CH NH to form the corresponding phosphoric ester of Formula I, whereby the symbols R R R X, Y, n and Hal have the meanings given above in Formulae I and III.

The cysteamine necessary for this process can also be formed in situ from ethyleneimine and hydrogen sulphide.

Because of the sensitivity of cysteamine to air, in this process it is advantageous to perform the reaction with the intermediate product of Formula V in an inert gas atmosphere, e.g. under an atmosphere of nitrogen. Also, decomposition of the cysteamine can be minimised or prevented if, in the form of addition salt, e.g. hydrochloride or hydrobromide, it is dissolved in an anhydrous solvent and then gradually converted into the free base by the addition of a stronger base such as gaseous ammonia, an it is reacted in this solution with the intermediate product of Formula V.

The two above described processes are preferably performed in the presence of solvents or diluents which are inert to the reaction partners, e.g. in the presence of ketones such as acetone, methylethyl ketone, ethers and ether-type compounds, alcohols, amides, hydrocarbons and halogenated hydrocarbons. If the reaction of the thiaz olinyl-pyridine derivative of Formula II, or of the cyanopyridine derivative of Formula IV, respectively, with a phosphorochloridate of Formula III is performed in the presence of a base, then both inorganic bases such as hydroxides or carbonates of alkali or alkaline earth metals or of ammonium as well as organic bases such as tertiary amines, are used. If a salt (oxide or mercaptide) of the thiazolinyl pyridine is used for the reaction, then chiefly the alkali and alkaline earth metal salts, the ammounium salt and the salts with strong organic bases are mentioned as such.

The new phosphoric esters of Formula I are stable substances, some of which are crystalline. They dissolve well in organic solvents. They form addition salts with inorganic acids, eg with halohydric acids such as hydrochloric acid, phosphoric acids, nitric acid, sulphuric acid, perchloric acid or with alkane sulphonic acids such as methanesulphonic acid and ethanesulphonic acid, or with alkylsulphuric acids such as methylsulphuric acid and ethylsulphuric acid.

The 2-hydroxyand Z-mercapto-S-thiazolinyl-(2')-pyridine derivatives of general Formula II which are used as starting materials, are new compounds. They can be prepared by various methods.

In a preferred method (a), the new 2-hydroxyand Z-mercapto-S-thiazolinyl-(2')-pyridine derivatives of the general Formula II are produced by reaction of a cyanopyridine derivative of the general Formula IV CN II J Y N (W) wherein R Y and n are defined as in Formula I, with cysteamine HS-CH CH NH Instead of reacting a cyanopyridine derivative of Formula IV direct with cysteamine, the former can first be converted with aliphatic alcoholes into the corresponding imino ethers in which the cyano group in Formula IV is replaced by a group wherein R is the radical of the aliphatic alcohol, and the imino ethers obtained can be reacted with cysteamine to form derivatives of Formula II.

The cysteamine required for this process and the variation thereof can also be formed in situ from ethyleneimine and hydrogen sulphide.

Because of the sensitivity of cysteamine to air, it is advantageous to perform the reactions with cysteamine in an inert gas atmosphere, e.g. under an atmosphere of nitrogen, or to prevent the decomposition of the cysteamine by dissolving it in the form of a salt, e.g. as hydrochloride, and liberating it in the reaction mixture by the continuous addition of a stronger base, e.g. by the gradual introduction of ammonia.

According to another method (b), the thiazolinyl pyridines of Formula II can be obtained by converting a cyanopyridine of Formula IV with hydrogen sulphide into a corresponding thioamide in which the cyano group of the cyanopyridine is replaced by the group and reacting this thioamide with a B-halogen ethylamine or with a salt of the latter to form thiazolinyl pyridines of Formula II.

In a method (c), the thiazolinyl pyridines of Formula II can also be produced by reacting the fl-hydroxyethylmide or a p-halogen ethylamide of a substituted pyridine carboxylic acid of the general Formula VI HY \N/ wherein R represents a hydroxyl group or a halogen atom, and R Y and n are defined as in Formula I, with phosphorus pentasulphide.

The methods (a), (b) and (c) described above for the production of the novel thiazolinyl pyridines of Formula II are preferably performed in the presence of solvents or diluents which are inert to the reaction components, e.g. in the presence of ketones such as acetone, methylethyl ketone, ethers, alcohols, amides, hydrocarbons and halogenated hydrocarbons etc.

The thiazolinyl-pyridines of the general Formula II are stable substances which crystallise well and are soluble in organic solvents.

The following non-limitative examples illustrate the invention further. The temperatures are given therein in degrees centigrade.

Example 1 (a) Gaseous ammonia is introduced for 1.5 hours into a solution of 192 g. of 2-hydroxy-S-cyano-pyridine and 233 g. of cysteamine hydrochloride in 1.5 litres of abs. ethanol at 1015. The reaction mixture is then refluxed for 10 hours under an atmosphere of nitrogen, after which it is filtered hot. The filtrate is cooled to 5 and the precipitate is filtered off. After recrystallisation from methanol, Z-hydroxy-S-thiazolinyl-(2)-pyridine melts at 187190.

(b) 20 g. of 2-hydroxy-5-thiazolinyl-(2)-pyridine are suspended in 120 ml. of methylethyl ketone and the suspension is then heated for 1 hour at 60 While stirring. 16.9 g. of dry potash are then added to this suspension and, after heating for 1 hour at 60, 23.5 g. of 0,0-diethyl phosphorochloridothioate are added dropwise at 70. The reaction mixture is then heated for hours at 75 and left to stand. The salt which precipitates is isolated and thoroughly washed with ether. The methylethyl ketone filtrate and the ether extracts are combined, shaken with ml. of 2 N aqueous sodium hydroxide solution and then Washed until the washing liquid is neutral. After drying, the mixture of solvents is distilled off and the residue is recrystallised from ether/petroleum ether. The O- 5- 2'-thiazolinyl -pyridyl-(2) 1 -0,0-diethyl phosphorothioate thus obtained melts at 54-57".

Example 2 (a) A suspension of 9 g. of 2-hydroxy-5-cyanopyridine and 8 g. of dry potash in 100 ml, of methylethyl ketone is stirred at 60 for one hour. Then, 14.2 g. of 0,0-diethy1 phosphorochloridothioate are added dropwise at the same temperature. The reaction mixture is stirred for 10 hours at 70-75", filtered, the precipitate washed with ether, and the filtrate evaporated. The residue is dissolved in ether, the ether solution shaken with 10 ml. of 2 N sodium hydroxide, washed with water and dried over sodium sulfate. After evaporating the ether the O-[S-cyano-pyridyl-2)]-0,0-diethyl-phosphorothioate is obtained as an oily substance which is sufiiciently pure for further use.

(b) Gaseous ammonia is introduced for minutes into a suspension of 7.4 g. of cysteamine hydrochloride in 100 ml. of methanol at 1015. The excess ammonia is then stripped off by sparging nitrogen into the mixture. 11.7 g. of O-[5-cyanopyridyl-(2) ]-0,0-diethyl phosphorothioate are added and the reaction mixture heated to reflux for 5 hours under an atmosphere of nitrogen. The mixture is evaporated to dryness, the residue treated with 50 ml. of Water and filtered. The product is recrystallised from methanol, and the O-[5-(2'-thiazolinyl)- pyridyl-(2)]-0,0-diethy1 phosphorothioate thus obtained melts at 5759.

Example 3 (a) A sample of the phosphorus compound prepared in Example 2(b) is dissolved in ether and the calculated amount of concentrated sulfuric is added dropwise in the cold. The precipitate is filtered off, washed with ether, and the O-[5-(2'-thiazolinyl)-pyridyl-(2)]-0,0-diethyl phosphorothioate hydrosulfate is thus obtained; M.P. 9294.

(b) By introducing hydrogen chloride into an ether solution of the phosphorus compound prepared in Example 2(b) and isolating the precipitate thus formed, the O-[5-(2'-thiazolinyl)-pyridyl (2)] 0,0 diethyl phosphorothiate hydrochloride is obtained; M.P. 84-87".

The phosphoric esters of the general Formula I listed in the following table are obtained in the way described in the Examples 1 to 3.

Physical No. Compounds constants.

1-..-. O-[5-(2-thiazolinyl)-pyridyl-(2)]-0,0-dimethyl 'ILD 1.5902

phosphcrothioate. 2. O-[5- (2-thiazolinyl) -pyridy1- (2) ]-O ,O-di-n-propyl M.P

phosphorothioate. 20-25. 3. O-[5-(2 thiazolinyl)-pyridyl-(2) [-0,0-di-n-butyl phosphorothioate. 4- O-[3-ehloro-5-(2-thiazolinyl)- ridyl-(2)]-0,0- M.P.

diethyl phosphorothioate 58-60". 5- O-[3bromo-5-(2-thiazolinyl)-pyridyl-(2)]-0,0- M.P.

diethyl phosphorothioate 86-87. 6- O-[6-methyl-5-(2thiazolinyl)-pyridyl-(2)]0,0-

dimethyl phosphorothioate 7. O-[6-methy1-5-(2-thiazolinyl)-pyridyl-(2)1-0,0-

diethyl phosphorothioate 8 0-[5- (2-thiazo1inyl) -pyridyl- (2)]-O-methy1-O-isopropyl phosphorothioate 9. O-[5-(2-thiazolinyl)-pyridyl- (2)]-0,0-dia1ly1 phosphorothioate 10- O-[5-(2-thiaz0liny1)pyridyl- (2)1-0 ,O-di-B-chlorw ethyl phosphorothioate 11- O-[5-(2-thiazolinyl)-pyridyl-(2)]-0,0-dimethoxyethyl phosphorothioate 12- O-[5-(2-thiazolinyl)-pyridyl-(2)]-0,0-dimethyl phosphate 13- O-[5-(2-thiaz01inyl)-pyridyl-(2)]-0,0-diethyl phos- M.P.

phate 8890. l4 O-[5-(2-thiazolinyl)-pyridyl-(2)]-0,0-di-n-propyl phosphate 15- S-[5-(2-thiazolinyl)-pyridyl-(2)]-0,0(limetl1yl phosphorothioate l6 S-[5-(2-thiazolinyl)-pyridyl-(2)]-0,0-diethyl phosphorothioate 17 S-[5-(2 -thiazo1inyl)-pyridy1- (2)]-0,0-dimetl1yl phosphorodithioate 18- S-[5- (2 -tl1iazolinyl)-pyridy1-(2)]-0,0-dicthyl phosphorodithioate Action on larvae of Boophzlus mzcroplus (cattle t1ck).- A number of 100 larvae of Boophilus microplus (age 2-4 weeks) of the DELNAV-resistant Ridgeland strain (Table 1) or of the DIAZINON-resistant Las Guerisas strain (Table 2) are placed on a round filter paper of 11 cm. diameter which is then laid in a Patri dish of 15 cm. diameter the bottom of which has been previously covered with 3 ml. of a solution of one of the test substances listed in column 1 of the tables, infra, in acetone/ water (volume ratio 1:20) in a concentration of 0.002% of test substance calculated on the weight of the solution. Another 4 m1. of this solution are applied on the filter paper bearing the larvae and a second filter paper is laid on top of the larvae. 3 ml. of the solution of test substance are applied on this second filter paper. After 10 minutes, the larvae are placed on a fresh filter paper and kept at room temperature and at relative humidity. The number of immobilised larvae is determined after a period of 3, 4, 6, 8, 15 and 24 hours.

TABLE 1 Concentra- Numbers of larvae in percent Concentra Numbers of larvae in percent tion of test immobilised aftersubstance, Test substance percent 4 hours 6 hours 8 hours O-[5- (2thiazolinyl) -pyridy1- (2)]-0,0-diethy1 phosphorothioate 0. 002 41 93 O'[3,5,6-trichloropyridyl-(2)]-0,0-diethyl phosphorothioate (known from U.S. Patent No. 3,244,586) 0. 002 25 57 82 Action on oviposition and hatching of female cattle ticks (Boophilus microplus).A number of 10 engorged female ticks of Boophilus mzcroplus (cattle tick) of the resistant Biarra strain are dipped for 3 minutes into a solution of one of the test substances listed in column 1 of the table, mfra. To prepare this solution the calculated amount (calculated on the weight of the solution) of test substance is dissolved in acetone and diluted with water to yield an acetone/water mixture having a volume ratio of about 1:20. The ticks thus treated are lightly dried on filter paper, placed into test tubes and kept at 27 C. and 85% relative humidity. The activity of a test substance is measured by determining the number of ovipositioning ticks and the rate of hatching of larvae from the eggs of the treated ticks. Oviposition is controlled 15 The active substance is intimately mixed and milled after 5, 10 and 15 days. with the emulsifier and the kieselguhr and then the cal- TABLE 3 Concentrationof test Numberof substance, ovlposition- Hatching Activity, Test substance percent ing ticks rate percent O-[5-(2'-tl1iazolinyl)-pyridyl-(2) ]-O, O-

diethyl phosphorothioate 0. 05 4 100 O-[2-isopropyl-4-methylpyrimidyl-(6) O, O-dicthyl phosphorothioate (Diazinou) (known from British Patent No. 713,273) 0. 05 10 0 The insecticidal and acaricidal compositions containcium sulphate is mixed in. A sprinkling agent which is ing the new active substances of general Formula I are particularly suitable for floor disinfection is obtained. produced in the known way by thoroughly mixing and Wettable poWders.-The following components are milling the active substances of general Formula I with used to produce (a) a 50% and (b) a 10% wettable suitable carriers, optionally with the addition of disperspowder: ing agents or solvents which are inert to the active sub- 95 (a) stances. The new active substances can be worked up 0 50 parts of OHZZHMZOHHYI) pyridyl (2)] into the following forms for use: diethyl phosphorothioate, Solid forms: dusts, sprinkling agents, granulates (coated 5 parts of naphthalene SulphOnic acid/ phenol sulphonic granules, impregnated granules, homogeneous granules; acid/formaldehyde condensate (average molar ratio Water dispersible concentrates of active substance: Wettable powders, pastes, emulsion; 5 parts of Champagne chalk, Liquid forms: solutions, aerosols. 20 parts of kieselguhr,

The concentration of active substance in these composi- 15 parts of kaolin, tions is 0.01 to 80% calculated on the weight of the com- 5 parts of sodium oleoyl methyl tauride. position. Other biocidal active substances or agents can (b) be admixed with these compositions. Thus, to broaden the range of action, the new compositions can contain, 10 Parts Of y py y for example, other insecticides and acaricides, also fungidiethyl P p cides, bactericides, fungistatics, bacteriostatics or nemato- 3 Parts of a miXwfe 0f the Sodium Salts of Saturated fatty cides in addition to the active substances mentioned of alcohol sulphates, general Formula I and the salts thereof. The compositions 5 Parts Of Sodium methylene bls-naphthalene sulphonate, according to the invention can also contain fertilisers, 82 Parts Of kaolin trace element? The active substances are intimately mixed with the The Q forms for apphfiatlon of the lrfsectlcfdal carriers and dispersing agents in suitable mixers and he and acancldal agents further Illustrate mventlon; mixture is milled in corresponding mills and rollers. Wetotherwlsfi expressly, stated H mean Parts table powders are obtained which can be diluted with by Welght An percentages glvel} therem F? calculated water to form suspensions of any concentration desired. 0n the total Welght the fespectlve Composltlon- Such suspensions can be used for controlling insects Dust.--The following components are used to produce which cause damage by eating and Sucking as well as (a) a 10% and (b) a 2% dust: for controlling ticks in pets and domestic animals.

(a) Emulsion concentrate.To produce a 25% emulsion 10 parts of O [5 (2-thiazolinyl)-pyridyl-(2)] 0,0- on entrate dimethyl phosphorothioate, 5 parts of finely dispersed silicic acid having a particle 25 Parts of 4111320111134) y y )1 size of about 25 m and a density of 2.2 (commercialmethyl P P ly available under the trademark Aerosil), Parts of eplchlorqhydrm, 35 parts of talcum; 5 parts of a composlte emuls1fier consisting of the con- 09) ((iensanon product of ogtyilplhoanol 3nd let 113 161218 gXldle avera e mo ar ratio 0 an ca cium o ecy 2 P2915 of O [5 (2"t h1aZhny1) Pyndyl phenyl sulphonate, in a weight ratio of about 1:1,

dimethyl phosphorothioate, 675 parts of Xylene 1 part of finely dispersed silicic acid having a particle size of about 25 m and a density of 2.2 (commercialare mixed together. This concentrate can be diluted with ly available under the trademark Aerosil), 7 water to form emulsions of concentrations suitable for the 97 parts of talcum;

protection of plants and stores. In particular, such emulsions are suitable for the controlling of ticks in pets and domestic animals.

We claim: 1. A compound selected from an ester of the formula X S R 0 X I" l l N wherein R and R independently of each other represent lower alkenyl or a lower alkyl radical any substituent of which is selected from halogen of an atomic number of at most 35 and lower alkoxy,

R represents hydrogen, halogen and an :atomic number of at most 35 or lower alkyl,

each of X and Y represents oxygen or sulfur, and n represents an integer ranging from 1 to 2, and an addition salt thereof with an inorganic mineral acid, a lower alkyl sulfonic acid, or a lower alkyl sulfuric acid. 2. A compound as defined in claim 1, wherein said ester is O-[5-(2-thiazolinyl) pyridyl (2)] 0,0 diethyl phosphorothioate.

References Cited UNITED STATES PATENTS 3,244,586 4/1966 Rigterink 260294.8

ALAN L. ROTMAN, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent 3.535.325 Dated October 20 1970 Kurt Gubler, Urs Meyer, Hans Ulrich Brechbuhler Inventor(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 9, line 16 "and" should read of Signed and sealed this 28th day of March 1972.

(SEAL) Attest:

EDWARD M.FLETGHER,J'R. ROBERT GOTTSCHALK Commissioner of Patents Attesting Officer USCOMM- DC 6037 6-?69 FORM PC4050 (10-69) er u 5. GOVERNMENT nmmnc ornc: [Ill 0-366-834 

